BS Microbiology Weber State College 1976
MS Virology/Biology Utah State University 1979
PhD Cell Biology Medical College of Wisconsin 1988
Postdoctoral Fellow at Johns Hopkins University

Current Research Interest: Understanding the functional role of the Extracellular Matrix in development, injury and repairin the Heart, Eye and Inner Ear Structures.

Versican and Heart Developmental Biology:

Versican is a proteoglycan of the extracellular matrix (ECM). Our lab has mainly worked on Vcan’s role in heart development, however, more recently through active extramural and intermural collaborations we are determining how Vcan plays a role in adult heart disease, vitreoretinal degenerative disorders and hearing loss.
My specific interest in versican’s (Vcan) role in the cardiovascular system began eighteen years ago at John’s Hopkins Medical Institute with a very interesting embryonic lethal insertional mutant mouse (heart defect; hdf) that dies at embryonic day E10.5 from severe heart defects. Because the hdf transgene contained a lacZ reporter, we could visualize expression of the gene during development in the heterozygous animals. Besides the heart Vcan -lacZ expression is highly and specifically expressed in the eye, limb bud, whisker follicles and the inner ear. For the last several years we have focused on different aspects of the role of Vcan in congenital heart disease with funds from a Grant-in-Aid from the American Heart Association and grants from the National Institute of Health NHLBHL66231-13.

Loss of Endocardial Cushions: Initially we were astonished to find that the primordia (endocardial cushions) of the heart’s septa and valves are completely missing in the homozygous hdf insertional mutant mice lacking Vcan. To understand the genetic basis of embryonic lethal defect, I mapped the transgene insertion to a region of mouse chr13 using fluorescence in situ hybridization and then specifically mapped the hdf locus near the Vcan gene by interspecific backcross analysis using a suitable polymorphism. Sequence analysis of an hdf genomic library pinpointed the transgene disruption between exon 7 and exon 8 of the Vcan gene creating a functional null.

Discovery of the Embryonic Second Heart Field: In addition to the surprising finding, that loss of Vcan eliminates the heart’s cushion primordia for the septa and valves, we made another observation that the cardiac outlet (right ventricle and arterial trunks) had failed to form. This led us to re-evaluate the assumption that this region of the heart is derived directly from the primary hearts fields. Our fate mapping studies combined with the work of Dr. Robert G. Kelly (Developmental Biology Institute of Marseilles, Luminy) and Dr. Margaret Kirby (Duke University) provided data for a fundamental paradigm shift in heart development that showed the cardiac outlet is derived from a second anterior heart field. Versican is therefore fundamentally important for formation of the outlet region, a site of approximately 1/3 of all live heart birth defects in humans.

Vcan in second heart field

Role for Vcan in the Adult Heart before and after Cardiac Injury: Recently, in an ongoing collaboration with Dr. Claude Le Saux, an expert in collagen deposition and fibrotic disease at the University of Texas Health Science Center in San Antonio (UTHSCSA), we unexpectedly found changes in collagen and other ECM proteins in the Vcan mutant models after coronary ligation injury. This finding indicated a previously unrecognized effect that altered Vcan variant expression has on regulating the organization of the ECM and collagen production that we are actively pursuing.

Vcan mutant after coronary ligation injury

Vcan mutations cause Vitreoretinal Degenerative Disorders in humans: In collaboration with Dr. Dieter R. Zimmermann (Zurich) we are exploring the underlying mechanism through which the single point Vcan mutations result in this degenerative disorder using mouse models of Vcan depletion.

H&E image of the hdf mouse retina

Role for Vcan in the Cochlea during Aging and after Injury: Recently, in collaboration with Dr.Hainan Lang (Pathology; MUSC), and with new funding from the National Institute of Health, we have become interested in the function of Vcan in the aging cochlea and after injury induced hearing loss.

Vcan (green) inner ear

Extramural Grants/Award Amount:

Current/Ongoing:

12/01/2000-1/31/2014 NIH/NHLBI-11 R01 HL66231 (Mjaatvedt PI, 70%) Cspg2 Gene and Cardiac Outlet Morphogenesis. The focus is to investigate the role of versican during cardiac outlet morphogenesis. Total funds: $1,825,000